Differentiated blood cells are formed from hematopoietic (blood-forming) pluripotent stem cells via intermediate stem cell-derived progenitor cells. Differentiated blood cells can be classified as red blood cells (RBC) or erythrocytes and white blood cells (WBC) or leukocytes. The blood also contains platelets that are detached cell fragments of much larger cells called megakaryocytes. The erythrocytes' main function is to transport oxygen and carbon dioxide bound to hemoglobin. White blood cells are grouped into three major categories including granulocytes, monocytes, and lymphocytes. Based on their morphology, granulocytes are also subdivided into three classes i.e. neutrophils, basophils and eosinophils. The monocytes mature into macrophages that together with neutrophils are the major phagocytes playing important roles in fighting infection. There are two classes of lymphocytes, i.e. T lymphocytes and B lymphocytes, both significantly contributing to immune responses.
Clonogenic committed hematopoietic progenitors give rise to the formation of homogenous populations of blood cells. For example, granulocyte-colony forming unit (CFU-G) cells give rise to a homogenous population of neutrophils, basophils and eosinophils. M-colony forming unit (CFU-M) cells give rise to a homogeneous population of macrophages, while granulocyte, macrophage-colony forming unit (CFU-GM; also often indicated as GM-CFU) cells give rise to macrophages and various subclasses of granulocytes.
There are many diseases and treatment regimens that can lead to anemia and some form of cytopenia often leading to further deterioration of physiological condition. These include hematopoietic cancers, solid cancers that metastasized to the bone marrow, AIDS, and treatments with radiation or chemotherapy. Most established anticancer and many anti-HIV drugs produce severe myelotoxicity that limits their clinical usefulness. In fact many prospective drug candidates cannot be introduced into the clinical practice because of their bone marrow toxicity that in most cases results in neuotropenia or thrombocytopenia.
There are relatively few safe tools to help recovery of bone marrow function during or after intensive radiation or chemotherapy. Erythropoietin (EPO) at doses of 150-300 Unit per kg administered three times a week is effective in reducing anemia and the requirement for blood cell transfusion. However, EPO does not significantly affect formation of platelets or blood cells of myeloid origin. In contrast, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) can reduce the duration and severity of cyclophosphamide-induced neutropenia. Ballestrero, A., Ferrando, F., Garuti, A., Basta, P., Gonella, R., Stura, P., Mela, G. S., Sessarego, M, Gobbi, M. and Patrone, F., “Comparative effects of three cytokine regimens after high-dose cyclophosphamide: Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and sequential interleukin-3 and GM-CSF,” J. Clin. Oncol., 17, 1296-1303 (1999).
Thrombopoietin (TPO), initially described as a regulator of megakaryocyte and platelet formation, is a growth factor that accelerates the recovery of all hematopoietic lineages following myelosuppressive therapies and that can expand hematopietic stem cells after transplantation. Fox, N., Priestley, G., Papayannopoulou, T. and Kaushansky, K., “Thrombopoietin expans hematopoietic stem cells after transplantation,” J. Clin. Invest., 110, 389-394 (2002). However, such role so far could be proved only for endogenous TPO; unfortunately, TPO administration not only failed to promote hematological recovery after chemotherapy or bone marrow transplantation, but it was also shown to cause immunological complications.
Amifostine is another drug that protects normal blood profile in paclitaxel-treated endometrial cancer. Dai, D., Holmes, A. M., Nguyen, T., Davies, S., Theele, D. P., Verschraegen, C. and Leslie, K. K., “A potential synergistic anticancer effect of paclitaxel and amifostine on endometrial cancer,” Cancer Res., 65, 9517-9524 (2005). This agent, however, only prevents drug-induced death of differentiated blood cells and does not promote hematopoiesis.